Anthelmintic polymethylenepiperazine and method of using same



United States Patent AJNTHELMINTIC POLYMETHYLENEPIPERAZINE AND METHOD OF USING SAME Frederick L. Bach, Jr., and Redginal I. Hewitt, Pearl:

No Drawing. Application May 16, 1956 Serial No. 585,160

6 Claims. (Cl. 167-55) This invention relates to new compositions. offmatter. More particularly, it relates to therapeutic compositions of polymethylenepiperazine-and a carrier. for the elimination of helminths such as pinworms andascarids.

An object. of; the present-invention: is; to 'prepare a composition-capable: of producing; ;a 'high .blood level and being: eilective' against :helminthst such: as; pinworms: and ascarids. A-- furtherobject is-to prepare a composition which will maintain a high;blood level.- of druggforv a longer period of time. A still. further object is to prepare a composition-whichz will be. absorbed less completely and/or more slowly in-order to reach and afiect helminthls: such as:- pinwormstand? ascarids-i in. the more terminal portions of the digestivettractf. 1

Wet have now found that: the: above. objects: can. be attained. by theme: of:polyrnethylenepiperazine, whichi'i's effective? in:. removing hehninths; particularly.- pinworms and ascarids. While pipera'zinehexahydrate? hastbeen used in the past for pinworms; it has the undesirable property of being hygroscopic, and, therefore, it is troublesome to combine with other materials, such as a carrier. On the-other hand, polymethylenepiperazine-is -a-stable,- tastelss; granular powder; insoluble in" water, which can be" easilymixed with other materials. Poly/methylenepiperazine, being substantially tasteless, is= more palatable than piperazin'ehexahydrate. When both'fediiand fasted dogs are given a single oral dose of. polymethyle'ne piperazine (50-100 mg./kgm.)*the peak blood level was reached five to eight hours after-administration. In contrast, piperazine, under similar conditions, reaches peak blood levels during the second hour after" administration. Furthermore; the presenceof polymethylenepiperazinei in the blood was detectable up to"'24 hours. after administrae tion;;whereas the'presenceofpiperazine'was not-so detectable; The. following table summarizesthisinforma tionz' TABLEI Piperazine blood 'levels in non-fasted dogs [Base equivalent dose: 100 mgr/kgm: oral]? Tests to determine excretion showed that 100% of the piperazine administered was excreted in the urine, whereas, of the polymethylenepiperazine administered, about 2. 60% was excreted in the urine and about 30% detected by assay in the faeces. Polymethylenepiperazine offers therapeutic advantages: over other forms. of piperazine, since it gives desirable blood levels for longer periodsof 5 time against'worms in the tissues, and its slower and/0r less. complete absorption favors greater elfectiveness in treating pinworms and other worms infecting the lower intestinal tract.

The amount of single doses or daily doses to be given will vary with the size of the man or animal to be treated, but should'b'e such' as to give a proportionate dosage of 1 to 500mg. per kgm. of body weight. ln terms of total weight of drug, this is usually from about 0.1 g. to 10.00. g. per dosageunit. In largeranimals, obviously, largerjdosage units maybe desirable.

' The compound polymethylenepiperazine was described in Beilstein, volume XXIII, page 6, 1936, quoting Rosdalsky, I. Prak. chem. (2) 53,'p. 22 (1896) and Berichte, volume 30, pages3043-3045. The compounds described in these references .are a polymethylenepiperazine of the following unit structure Its use as an anthelmintic in the treatment of pinworms or ascaridshas not been described. Methods of pre.- paring the compound are described in the above reference and in the= chemical literature.

Polymethylenepipera'zine was given in a single, oral dose to-mice naturally infected with pinworms of the species Aspicularis tetraptera, which resembles human pinwornis. The mice were killed and necropsied several days after treatment and the intestinal tract examined foiapinworms. Activity is'indicated when a large proportion. ofthe. treated. miceireveal few or no worms at necropsy, as compared withuntreated controls. The followlng Table ll illustrates the results obtained:

TABLE II Percent of j Single oral mice with Compound Test N0. dose, N0. Sur- O-5 worms I mgz/kgm. vivals at necropsy- Aspiculuris Polyrnethylene- 3453B39 500 10110 100 1.0/10 100 10/10 90 10,110 100 10/10 80 10/10 lO/lO 0 10/10 60 10/10 40 10/10 30 10/10 20 9/10 22 Polymethylene- 10/10 100 piperazme.

The present compositions containing polymethylenepiperazine are effective against dog ascarids (Toxocara canis), as shown in Table III illustrating the results obtained and also comparing them with piperazine hexahydrate and piperazine hydrochloride.

TABLE III Efiects of polymethylenepiperazine against dog ascarids (Toxocara canis), as compared with piperazine hexahydrate and hydrochloride After- No.

Ascarids Percent Dog. Oral Dose, Total Retained Ascarids No. mgJkgm. 1st 2nd 3rd. at N ec- Passed Dose Dose Dose ropsy (Total) 214 Polymethylenepiperazine"..- 12.5, b 25 19 a 4 23 100 d 12. 5, 25, b 50 7 3 3 13 l 93 12. 5, 25, b 50 0 1 3 4 0 100 a 100 10 6 63 906 Piperazine hexahydrate. a 100 9 9 1 90 922 do 100 4 4 4 50 130 do 100 6 6 1 86 127 Piperazine hydrochloride. 5 100 9 9 15 40 a Single dose.

Sequential treatment, single doses, with seven days rest between increments.

a Died third day after second dosecause of death unknown. d Three-eight days after last dose. No emesis noted with any of the doses used.

Polymethylene piperazine is also effective against Ascaris lumbricoides in guinea pigs. A summary of tests carried out is shown in Table IV.

TABLE IV Effects of polymethylenepipearzine against larval Ascaris lumbricoides in guinea pigs Experimentally infected with 2000 embryonated A. lumbricqides ova per animal.

Approximately one week after inoculation.

The compound polymethylenepiperazine can be combined with a carrier and dispensed in any of the usual dosage unit forms of pharmaceutical preparations; for example, tablets, capsules, pills, suspensions, as a powder, or in any other desirable form in the therapeutic quantities hereinbefore given. It may be in a dosage unit form for a single, daily, therapeutic dose or in smaller units for multiple doses or in larger units for division into single doses. Obviously, in addition to the therapeutic product, there may be present excipients, binders, fillers and other therapeutically inert ingredients necessary in the pharmaceutical preparation.

For use in treating animals it may be combined with edible carriers, such as feed stuffs, etc.

We claim:

1. A therapeutic composition useful in the treatment of helminths in dosage unit form comprising from 0.1 g. to 10.00 g. of a polymethylenepiperazine of the following unit structure per dosage unit and an edible carrier.

2. A therapeutic composition for oral administration useful in the treatment and elimination of pinworms and ascarids in dosage unit form comprising from 0.1 g. to

10.00 g. of a polymethylenepiperazine of the following unit structureper dosage unit and a pharmaceutical carrier.

3. A therapeutic composition useful in the treatment of pinworms and ascarids in dosage unit form comprising from 0.1 g. to 10.00 g. of a polymethylenepiperazine of the following unit structure and a solid pharmaceutical carrier, said composition being in tablet dosage unit form.

4. A therapeutic composition in dosage unit form useful in the treatment of pinworms and ascarids comprising from about 0.1 g. to 10.00 g. of a polymethylenepiperazine of the following unit structure and a significant amount of pharmaceutical carrier.

5. A method of maintaining higher blood levels of piperazine useful in the treatment of pinworms and ascarids which comprises administering in dosage unit form from 1 mg. to 500 mg. per kgm. of body weight of a polymethylenepiperazine of the following unit structure N H N-on v and an edible carrier.

References Cited in the file of this patent White: British Med. Iour. No. 4839, October 3, 1953, pp. 755-758. 

1. A THERAPEUTIC COMPOSITION USEFUL IN THE TREATMENT OF HELMINTHS IN DOSAGE UNIT FORM COMPRISING FROM 0.1 G. TO 10.00 G. OF A POLYMETHYLENEPIPERAZINE OF THE FOLLOWING UNIT STRUCTURE 